Damage to healthy tissue is both unintended and expected when radiation therapy is used to treat neoplastic disease in the eye. Last month EyeNet discussed the diagnostic pitfalls for radiation retinopathy, detailing in particular the perspective of James J. Augsburger, MD, professor and chairman of ophthalmology at the University of Cincinnati. In general, the severity of vision loss from radiation tends to worsen with higher dosages of radiation, larger tumors, posterior tumors or those located closest to the macula or optic nerve, Dr. Augsburger said. But since there is no universally agreed-upon classification system for radiation retinopathy, assessment of the true effects of treatments in clinical studies is a challenge. In Part One of this story, Dr. Augsburger provided descriptions of radiation retinopathy, radiation optic neuropathy, radiation choroidopathy and radiation intraocular tumor vasculopathy and proposed that all of these come under the umbrella term “radiation fundopathy.” He believes this may be the most useful foundation for a classification system. (Look for Part One in March’s EyeNet at www.eyenetmagazine.org.)

A complementary description of tumor characteristics and their relationship to the dose of radiation was published last year in the American Journal of Ophthalmology. “Radiation Maculopathy After Ophthalmic Plaque Radiation for Choroidal Melanoma” was authored by Paul T. Finger, MD, and colleagues.1 Dr. Finger is a clinical professor of ophthalmology at New York University and director of the ocular tumor service at The New York Eye and Ear Infirmary.

Confounding factors. Martine J. Jager, MD, PhD, senior medical specialist in the department of ophthalmology at Leiden University in the Netherlands, said that confounding the creation of a classification system is the fact that the wide variety of radiation techniques used at different medical centers makes it difficult to assess treatments for radiation retinopathy in a standardized way in clinical trials.

And further complicating the picture are coincident pathologies such as diabetic retinopathy or coincident treatments with chemotherapy, which are not uncommon in this patient population, added James Kinyoun, MD, professor of ophthalmology at the University of Washington in Seattle.

Treatments Emerging, Nevertheless

In spite of the contention attending definitions of collateral radiation injury, several studies for the mitigation of injury have shown promise.

Prophylaxis. Some small studies suggest that laser photocoagulation given prior to the onset of retinopathy might prevent vision loss.2,3,4 But the benefits are arguable. “I would say that laser photocoagulation helps some of our patients, but the improvement is minimal. It’s not dramatic or marked,” Dr. Kinyoun said.

In other preventive efforts, injections of periocular triamcinolone were given at the time of plaque radiation. One study found that 55 patients treated with 40 mg triamcinolone at the time of radiation and again four and eight months afterward had lower rates of macular edema compared with 32 nontreated patients.5 There was no final difference, however, in vision loss. A larger study found that 108 patients treated with triamcinolone at plaque application and twice afterward not only had significantly less macular edema over 18 months of follow-up than a control group of 55 patients but a lower incidence of vision loss as well.5

Postradiation treatment. More compelling are efforts to manage postradiation retinopathy, including laser photocoagulation, intravitreal anti-VEGF agents and steroids such as triamcinolone acetonide. As with prophylactic gestures, studies of these treatments have been small and nonrandomized and so far have documented minimal benefits, according to Dr. Jager. Small studies on laser photocoagulation, for example, have suggested that recovery of vision may be modest, limited to certain patients and not sustained long-term.

Anti-VEGF on the horizon. But a number of trials testing intravitreal anti-VEGF agents and corticosteroids have been more intriguing. Small, nonrandomized studies have shown that intravitreal triamcinolone can maintain or improve visual acuity.5 A case series presented at the Academy’s 2008 Annual Meeting evaluated 124 patients with radiation retinopathy treated with bevacizumab over one year and found that a mean visual acuity of 20/100 at baseline had improved to 20/40 at 12 months, said Timothy G. Murray, MD, MBA, one of the session presenters and professor of ophthalmology and radiation oncology at the Bascom Palmer Eye Institute.

Dr. Finger recently reported the first study on intravitreal ranibizumab for radiation maculopathy. That phase 1, open-label study of five patients found that treatment with intravitreal ranibizumab reduced intraretinal hemorrhages, exudation and macular edema. After a mean of 8.2 injections given over a mean of eight months, BCVA in four patients increased by an average of six letters.6

Dr. Finger, who proposed a classification system for radiation retinopathy in 20051 and reported that anti-VEGF agents could reverse the effects of radiation retinopathy, noted that patients who receive anti-VEGF agents usually need treatments in four- to eight-week intervals to maintain the beneficial effects. “I have had a few rare patients who are on three-month intervals, and in just a few patients, I’ve been able to stop treatment without vision loss,” he said. “Most patients are committing to an open-ended course of intravitreal injections. That is not easy for them and is dependent on how motivated they are to regain or retain sight.”

Outcomes are better for those treated as early as possible. Dr. Finger said the prognosis for vision in patients who have undergone plaque radiation for anterior and nasal uveal melanoma is more favorable—and the plaque radiation is less likely to cause irreversible vision loss—than for those who are treated for posterior temporal melanomas. In last year’s AJO report, Dr. Finger and colleagues reported that patients with posterior tumors are at greater risk for irreversible vision loss from retinopathy because the radiation dose is higher to the fovea and macula.1 Patients with long-standing macular edema or fibrosis tend to experience little or no recovery of vision, Dr. Finger said.

Combining approaches, polishing goals. Dr. Murray is currently working to zero in on which patients respond best to anti-VEGF therapy, and to determine the optimal duration of treatment. He has also tried, with some success, combination therapy with intravitreal steroids and anti-VEGF agents in a few patients. While anti-VEGF agents decrease leakage and suppress neovascularization, steroids help resolve inflammation and may stabilize the retinal vasculature, he said.

More Iatrogenesis?

Ironically, these treatments for an iatrogenic complication can themselves pose iatrogenic complications.

There is a slight risk of endophthalmitis with intravitreal injections, but Dr. Murray and colleagues found that this complication was quite rare at Bascom Palmer—only one case occurred after 10,142 intravitreal injections. He said a standardized injection protocol and adherence to sterile technique can prevent endophthalmitis.

A larger concern is the effect of applying drugs to eyes that have contained a tumor and which may harbor remaining melanoma cells. This should be considered with particular care, Dr. Jager said, adding that so far the concern has not materialized. Along with fellow researchers at the Leiden University Medical Centre, she found that neither triamcinolone acetonide nor anecortave acetate had an effect on tumor cell growth when tested on three uveal melanoma cell lines in vitro. (Anecortave acetate, an angiogenesis inhibitor, could be an alternative for treating radiation retinopathy, she said.)

Distinguishing success from natural history. Treatments such as anti-VEGF agents and steroids may reduce edema and retinal thickening in some patients, Dr. Augsburger acknowledged, but he said that these conditions can also improve spontaneously. “Some patients with small tumors far from the focusing center of the eye will develop leakage in and around the macula, but after about six months or so their vision stabilizes,” he said.

Dr. Finger differed, however, saying that inflammation-induced cystoid macular edema should not be confused with radiation retinopathy. “CME commonly lasts six months and stabilizes. Radiation maculopathy typically occurs 18 months after exposure and is progressive.”

Future Management

Tara McCannel, MD, PhD, and colleagues have found that in cadaver eyes, silicone oil attenuates the radiation absorbed by nontumor tissue by approximately 50 percent.7 “I am hopeful that this new discovery may help prevent or reduce the amount of damage caused by radiation before vision is lost,” she said. Dr. McCannel is assistant professor of ophthalmology and director of ophthalmic oncology at the University of California, Los Angeles. Vitrectomy with silicone oil placement is now an option for patients undergoing radiation plaque melanoma therapy at the Jules Stein Eye Institute.

Dr. Finger said that clinicians should understand the specific applications of silicone oil in serious detail. “The attenuation of silicone is thickness-dependent. The doses absorbed by nontumor tissue will be diminished according to how much silicone is present between the source and the normal tissue. You can’t put one number on all tissues. You can put a number on points of interest, such as the opposite eye wall, the fovea, the optic nerve or the lens. But you have to calculate the distance from the plaque and then calculate how much it actually reduces the dose,” he said.

Dr. McCannel’s work also suggests that parameters such as contrast sensitivity may be affected before visual acuity, bolstering the notion of treating patients early, before retinopathy is apparent to the patient. Dr. Murray added, “We now realize that radiation retinopathy appears earlier than has been previously recognized in patients undergoing radiation therapy. Patients may have minimal visual decline but significant findings on SD-OCT. A decline in vision that’s associated with vascular leakage in the fovea or macula on SD-OCT imaging is an indication that treatment may be helpful.”
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Dr. Finger holds a patent for the use of anti-VEGF treatment for radiation-induced vasculopathy and has received a grant from Genentech for related research. The other physicians report no related interests.